小宮根 真弓

<title>Abstract</title>A lysosomal transmembrane protein SLC29A3 transports nucleosides from lysosomes to the cytoplasm. Loss-of-function mutations of the SLC29A3 gene cause lysosomal nucleoside storage in monocyte/macrophages, leading to their accumulation called histiocytosis in humans and mice. Little is known, however, about a mechanism behind nucleoside-dependent histiocytosis. TLR7, an innate immune sensors for single stranded RNA, bind and respond to nucleosides. We here show that they drive nucleoside-mediated histiocytosis. Patrolling monocyte/macrophages accumulate in the spleen of <italic>Slc29a3</italic>^−/− mice but not <italic>Slc29a3</italic>^−/−<italic>Tlr7</italic>^−/− mice. Accumulated patrolling monocyte/macrophages stored nucleosides derived from cell corpse. TLR7 was recruited to phagosomes and activated as evidenced by TLR7-dependent phagosomal maturation. TLR7 induced hyper-responsiveness to M-CSF in <italic>Slc29a3</italic>^−/− monocyte/macrophages. These results suggest that TLR7 drives histiocytosis in SLC29A3 disorders. <sec><title>One Sentence Summary</title>SLC29A3 disorders are caused by activation of TLR7 with accumulated nucleosides in lysosomes. </sec>

Generalized pustular psoriasis (GPP) is a rare disease characterized by recurrent fever and systemic flushing accompanied by extensive sterile pustules. The committee of the guidelines was founded as a collaborative project between the Japanese Dermatological Association and the Study Group for Rare Intractable Skin Diseases under the Ministry of Health, Labour, and Welfare Research Project on Overcoming Intractable Diseases. The aim of the guidelines was to provide current information to aid in the treatment of patients with GPP in Japan. Its contents include the diagnostic and severity classification criteria for GPP, its pathogenesis, and recommendations for the treatment of GPP. Since there are few clinical trial data with high levels of evidence for this rare disease, recommendations by the committee are described in the present guidelines.

＜文献概要＞2007年1月〜2016年12月の10年間に,自治医科大学皮膚科で生検し偽リンパ腫と診断した27例を対象として,臨床像,皮疹および浸潤する細胞の特徴,治療法とその効果を検討した.初診時の平均年齢は54歳で男女差はなかった.単発16例,多発11例で,26例が顔面に生じていた.皮疹の性状は,22例で結節を形成していた.浸潤する細胞は,B細胞優位17例,T細胞優位10例であった.治癒を確認した21例を検討したところ,切除8例,生検のみ6例,ステロイド外用5例,ステロイド内服および外用1例,ステロイド局注1例であった.偽リンパ腫は良性疾患であり,生検のみでも消退を望めるため,まずは確定診断を目的とした部分生検を考慮すべきと考えた.

症例は72歳女性で、関節リウマチで通院中であったが、約7ヵ月前から左頬粘膜、下唇に水疱、びらんが出現した。扁平苔癬、自己免疫性水疱症などを疑い精査を行ったが確定診断には至らず、経過観察となった。その後、口腔内のびらんが拡大してきたため当科紹介となった。メトトレキサート(MTX)による口腔粘膜びらんを疑い、血液検査を施行した。その結果、白血球数、赤血球数、ヘマトクリット値の低値を認めた。汎血球減少を伴う口腔粘膜潰瘍の診断で、直ちに主治医に連絡しMTXの中止を依頼した。MTXは直ちに中止となり、汎血球減少に対し入院下に輸血が行われた。口腔粘膜はMTX中止後に改善し、3週間後にはほぼ上皮化した。

Interleukin (IL)-33 can function both as a conventional cytokine and as a nuclear factor regulating gene transcription. IL-33 expression is strongly upregulated in the nucleus of keratinocytes and serum of patients with psoriasis. However, the role of IL-33 in psoriasis is unclear, and IL-33 expression in the lesional psoriatic skin after conventional systemic treatments has not been investigated. In this study, we aimed to compare IL-33 mRNA in patients’ lesional skin samples and IL-33 protein expression in patients’ serum before and after treatment with methotrexate (MTX) and narrowband ultraviolet B (NB-UVB). IL-33 mRNA levels in lesional skin and IL-33 protein levels in serum were downregulated after treatment with MTX. Results revealed a significant decrease in IL-33 protein expression (P = 0.028). IL-33 expression increased after NB-UVB treatment. IL-33 production is associated with inflammatory skin in psoriasis, possibly through its cytokine function. However, high expression of IL-33 after NB-UVB treatment suggests the occurrence of unknown functions to alleviate psoriatic lesions without IL-33 involvement.

A 92-year-old man developed an erythematous eruption on the trunk and extremities with numerous pustules accompanied by fever. He had never experienced pustular eruption or been diagnosed with psoriasis previously. Skin biopsy revealed Kogoj's spongiform pustule, and he was diagnosed with generalized pustular psoriasis (GPP). Genomic DNA was extracted from his peripheral blood and the sequence of IL36RN gene was analyzed, which revealed a p.Arg10X homozygous mutation. Several cases of elderly-onset GPP have been reported, however, this is the oldest case of GPP. The existence of splice variants of IL36RN was suspected, but we could not detect any splice variants of IL36RN in this case or in a healthy control from peripheral blood samples.

Mucosal melanoma is a rare aggressive cancer with a very poor prognosis. Clinical and pathological characteristics of mucosal melanoma differ from those of cutaneous melanoma and there are no established management guidelines for mucosal melanoma. Complete surgical excision is one of the most effective treatments for localized lesions, while targeted therapies and immunotherapies, such as monoclonal antibodies that target cytotoxic T-lymphocyte-associated molecule-4, and the programmed death (PD)-1/PD-ligand 1 pathway inhibitors, are treatment options for unresectable or metastatic lesions. Here, we describe the case of a patient with oral mucosal melanoma with multiple metastases. In our case, local injection of interferon (IFN)-β with dacarbazine–nimustine–vincristine therapy provided antitumor effects on an invasive tumor on the upper gingiva. Nivolumab therapy produced complete remission of lymph node and bone metastases. In contrast, the remaining in situ portion of oral mucosal melanoma on the hard palate was refractory to IFN-β monotherapy and nivolumab therapy. However, after administration of nivolumab, peritumoral injection of IFN-β showed rapid therapeutic effects. Our case suggested that nivolumab upregulated the antitumor effects of IFN-β, which induced the recruitment of CD8+ T cells into the tumor microenvironment contributing to the deletion of tumor cells. Combination therapy of IFN-β and nivolumab may be a potential treatment option for patients with oral mucosal melanoma.

＜症例のポイント＞乾癬性紅皮症の治療経過中にnarrow band ultraviolet B(以下、NB-UVB)照射療法を行い膿疱性乾癬が誘発された。IL36RN遺伝子変異検索ではp.Asn47Serのヘテロ変異を認めた。通常はキャリアと解釈されるヘテロ変異症例でもなんらかの複合要因のもとに炎症反応が強く働き、膿疱性乾癬の皮疹が発症する可能性があり、自験例は光線過敏症が要因と考えた。(著者抄録)

Apremilast, an oral, small-molecule phosphodiesterase 4 inhibitor, works intracellularly within immune cells to regulate inflammatory mediators. This phase 2b randomized, placebo-controlled study evaluated efficacy and safety of apremilast among Japanese patients with moderate to severe plaque psoriasis. In total, 254 patients were randomized to placebo, apremilast 20 mg b.i.d. (apremilast 20) or apremilast 30 mg b.i.d. (apremilast 30) through week 16; thereafter, all placebo patients were re-randomized to apremilast 20 or 30 through week 68. Efficacy assessments included achievement of 75% or more reduction from baseline in Psoriasis Area and Severity Index score (PASI-75; primary) and achievement of static Physician Global Assessment (sPGA; secondary) score of 0 (clear) or 1 (minimal) at week 16. Safety was assessed through week 68. At week 16, PASI-75 response rates were 7.1% (placebo), 23.5% (apremilast 20; P = 0.0032 vs placebo) and 28.2% (apremilast 30; P = 0.0003 vs placebo); sPGA response rates (score of 0 or 1) were 8.8% (placebo), 23.9% (apremilast 20; P = 0.0165 vs placebo) and 29.6% (apremilast 30; P = 0.0020 vs placebo). Responses were maintained with apremilast through week 68. Most common adverse events (AEs) with placebo, apremilast 20 and apremilast 30 (0-16 weeks) were nasopharyngitis (8.3%, 11.8%, 11.8%), diarrhea (1.2%, 8.2%, 9.4%), and abdominal discomfort (1.2%, 1.2%, 7.1%), respectively. Exposure-adjusted incidence of these AEs did not increase with continued apremilast treatment (up to 68 weeks). Apremilast demonstrated efficacy and safety in Japanese patients with moderate to severe plaque psoriasis through 68 weeks that was generally consistent with prior studies.

We report a case of a 70-year-old woman with generalized pustular psoriasis (GPP) who responded well to infliximab therapy and adalimumab therapy after secondary failure of infliximab therapy, but did not respond to ustekinumab therapy. We speculate that the pathogenic factor in this case favored anti-tumor necrosis factor (TNF)- therapy to anti-interleukin-12/23 therapy. Herein, we also briefly present three additional cases of treatment with adalimumab after secondary failure of infliximab. GPP is often difficult to treat, and no placebo-controlled trials have been conducted to guide the use of biologics against it because of a paucity of cases. Infliximab and adalimumab are anti-TNF- antibodies that specifically block the interaction of TNF- with its receptors. Infliximab has been reported to be effective, with a rapid clearance of symptoms, even in cases of severe GPP. Adalimumab could be a good biologic candidate that can be administrated after secondary failure of infliximab therapy.

Background: Skin is the outermost tissue of the human body, and works as a mechanical, chemical, and biological barrier. The epidermis is the uppermost layer of the skin, and keratinocytes constitute the majority of epidermal cells. Wounds are disruptions of skin integrity, and cause tremendous disadvantages to humans; accordingly, rapid wound healing is very important. Interleukin (IL)-33 is expressed in barrier tissue cells, such as epithelial and endothelial cells. Upon injury, IL-33 is released to stimulate immune cells, functioning as an "alarmin." ST2 is a receptor for IL-33; its soluble form (s)ST2 acts as a decoy receptor and competes for IL-33 binding. Objectives: We aimed to clarify the role of IL-33 in wound healing. Materials and methods: Wild-type (WT), IL-33 knockout (IL33 KO) mice, and sST2 transgenic (Tg) mice were wounded with a 4-mm punch, and the wound healing process was compared. Immunohistochemical analyses were performed to detect macrophages, neutrophils, and mast cells. Total RNA was extracted from the skin samples and real-time PCR was performed. An in vitro scratch wound assay was performed. Results: Wound healing was delayed in IL33 KO mice compared to WT mice, while wound healing in sST2 Tg mice was comparable to that of WT mice. A histological examination showed delayed elongation of the epidermal tongue in IL-33 KO mice. An immunohistochemical study revealed prolonged neutrophilic infiltration at a later stage in IL-33 KO mice. IL-6, IL-1 beta, and CXCL1 transcripts were more abundant in the wounds of IL-33 KO mice than WT mice. Intraperitoneal administration of an NF kappa B inhibitor to IL-33 KO mice normalized the delayed wound healing and the enhanced expression of IL-6 in IL-33 KO mice. Epidermal keratinocytes from IL-33 KO mice showed delayed wound closure compared to those from WT mice. Conclusion: Our results indicate that nuclear IL-33, but not IL-33 as a cytokine, has beneficial effects on wound healing in mice, probably by suppressing NF kappa B to inhibit excessive inflammation and by maintaining keratinocyte proliferation or migration for epithelialization. (C) 2016 Japanese Society for Investigative Dermatology. Published by Elsevier Ireland Ltd. All rights reserved.